An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity

The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ<sub>9-21</sub> promotes Aβ<sub>42</sub> fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ<sub>9-21</sub> coassembles with Aβ<sub>42</sub>, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ<sub>9-21</sub> can alleviate the neurotoxicity of Aβ<sub>42</sub> in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.

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Journal
Nature Communications
Published
2025-07-01
DOI
https://doi.org/10.1038/s41467-025-60978-w
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.00

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article

An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity

Changdong He, Yuan Liu, Z. Xu, Xiaomeng Shi et al.
Nature Communications
Glycosylation and Glycoproteins Research
article

An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity

Changdong He, Yuan Liu, Z. Xu, Xiaomeng Shi, Suwei Dong, Wencheng Xia, Dangliang Liu, Qijia Wei, Fengzhang Wang, Cong Liu, Jun Zhang, Chu Wang, Xiaoya Wang, Lu Huang, Wenzhe Li
article en

Abstract

The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ<sub>9-21</sub> promotes Aβ<sub>42</sub> fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ<sub>9-21</sub> coassembles with Aβ<sub>42</sub>, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ<sub>9-21</sub> can alleviate the neurotoxicity of Aβ<sub>42</sub> in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.

Nature CommunicationsVol. 16(1)
Ningbo University (CN), Shanghai University (CN), Shanghai Academy of Social Sciences (CN), Peking University (CN), Shanghai Institute of Organic Chemistry (CN), Center for Life Sciences (CN), University of Chinese Academy of Sciences (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, Peking University, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Openalex Percentile: Top 86%
Glycosylation and Glycoproteins Research
DOIOpen Access PDFOpenAlex
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